Utilizing recombinant mRNA differential display a novel cDNA, termed Nebraska One (NEBR1), was cloned from HIV-1 infected monocyte- derived macrophages. NEBR1 functions as a transcriptional repressor with demonstrated anti-retroviral properties. Expressed copiously in HIV-1 infected mononuclear phagocytes (MP), NEBR1, could represent a unique innate immune. We hypothesize that NEBR1 is a natural cellular suppressor of HIV-1 that plays a role in both modulating macrophage function and viral infection during persistent disease. The relationship between NEBR1 and HIV-1 p24 expression in brain MP makes it of special interest to HIV-1 encephalitis and its associated dementia. To these ends we propose to elucidate: (1) the steps of HIV-1 life cycle in which NEBR1 suppresses HIV-1 replication (including HIV-1 entry, HIV-1 DNA synthesis, its genomic integration, and gene transcription from HIV DNA); (2) the DNA binding motif of NEBR1, and (3) the promoter/enhancer region(s) of NEBR1 that are activated by HIV-1. The intent of this proposal is to determine how NEBR1 is regulated and how it effects HIV-1 replication. The potential of NEBR1 to effect viral-host cell interactions is realistic, novel and contains therapeutic implications.